The Workings of NCI Nanotechnology Alliance for Cancer –an Opportunity for a New Class of Diagnostic and Therapeutic Solutions Based on Nanotechnology

NSF Nanoscale Centers Grantees ConferenceWashington, DC

December 5, 2007

Piotr Grodzinski, Ph.D.Director, NCI Nanotechnology Alliance

National Cancer Institute

We Must Accelerate Progress Against CancerWe Must Accelerate Progress Against Cancer

21.9

180.7

48.1

586.8

193.9

53.3

190.1231.5

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza

Cancer

19502003

Dea

th R

ate

Per

100,

000

Unlike Other Major Disease Killers, Cancer Continues to Take the Nearly Same Toll As In 1950

Source for 2005 deaths and diagnoses: American Cancer Society (ACS) 2005 Cancer Facts & Figures; Atlanta, GeorgiaSource for 2003 age-adjusted death rate: National Center for Health Statistics, U.S. Department of Health and Human Services, NCHS Public-use file for 2003 deaths.

Nanotechnology is an Enabler of New Solutions for CancerNanotechnology is an Enabler of New Solutions for Cancer

Early detection Imaging Therapy

• Molecular imaging and early detection

• In vivo imaging

• Reporters of efficacy

• Multifunctional therapeutics

• Prevention and control

• Research enablers

Focus Areas:

Highly talented multi-disciplinaryresearch teams

Sciences, medicine, and engineeringCompetition and collaboration

Synergy and difference

Can we build a bigger whole?

NCI Nanotechnology AllianceThe OpportunityNCI Nanotechnology AllianceThe Opportunity

• promote the development of state-of-the-art nanotechnologies for cancer applications

• accelerate the translation of the discoveries into clinically relevant diagnostics and therapeutics

Major Programs of the Alliance:

Centers of Cancer Nanotechnology Excellence

Multidisciplinary Research Teams• Training• Interagency Collaborations

Nanotechnology Platforms for Cancer Research

Nanotechnology Characterization Laboratory

1

2

3

4

NCI Nanotechnology Alliance - StrategiesNCI Nanotechnology Alliance - Strategies

NCI Nanotechnology Alliance - AwardsNCI Nanotechnology Alliance - Awards

Centers of Cancer Nanotechnology Excellence (8)

Cancer Nanotechnology Platform Partnerships (12)

Nanotechnology Platform for Targeting Solid Tumors, The Sidney Kimmel Cancer Center, San Diego, Calif.

Detecting Cancer Early with Targeted Nano-probes for Vascular Signatures, University of California, San Francisco, Calif.

Nanotechnology Platform for Pediatric Brain Cancer Imaging and Therapy, University of Washington, Seattle, Wash.

Near-Infrared Fluorescence Nanoparticles for Targeted Optical ImagingUniversity of Texas M. D. Anderson Cancer Center, Houston, Texas

Hybrid Nanoparticles in Imaging and Therapy of Prostate Cancer, University of Missouri, Columbia, Mo.

DNA-linked Dendrimer Nanoparticle Systems for Cancer Diagnosis and Treatment, University of Michigan, Ann Arbor, Mich.

MetallofullereneNanoplatform for Imaging and Treating Infiltrative Tumor, Virginia Commonwealth University, Richmond, Va.

Novel Cancer Nanotechnology Platforms for Photodynamic Therapy and Imaging, Roswell Park Cancer Institute, Buffalo, N.Y.

Multifunctional Nanoparticles in Diagnosis and Therapy of Pancreatic Cancer, State University of New York, Buffalo, N.Y.

Integrated System for Cancer Biomarker Detection, Massachusetts Institute of Technology, Cambridge, Mass.

NanotherapeuticStrategy for MultidrugResistant Tumors, Northeastern University, Boston, Mass.

Photodestructionof Ovarian Cancer: ErbB3 Targeted Aptamer-NanoparticleConjugate, Massachusetts General Hospital, Boston, Mass. Carolina Center

of Cancer Nanotechnology Excellence, University of North Carolina, Chapel Hill, N.C.

NanosystemsBiology Cancer Center, California Institute of Technology, Pasadena, Calif.

Center of Nanotechnology for Treatment, Understanding, and Monitoring of Cancer, University of California, San Diego, Calif.

Emory-Georgia Tech Nanotech-nology Center for Personalized and Predictive Oncology, Atlanta, Ga.

Nanomaterials for Cancer Diagnostics and Therapeutics, Northwestern University, Evanston, Ill.

The Siteman Center of Cancer Nanotechnology Excellence at Washington University, St. Louis, Mo.

Center for Cancer Nanotechnology Excellence Focused on Therapy Response, Stanford University, Palo Alto, Calif.

MIT-Harvard Center of Cancer Nanotechnology Excellence, Cambridge, Mass.

TiO2

Liposome

Gold nanoshell

Fullerene

Quantum Dot

Dendrimer

Nanoemulsion

Colloidal gold

Polymers

• Multiple functions• Tissue targeting

• Tumor-specific binding• Sensing or imaging capability

• Improved sensitivity• Multi-modal imaging

• Non-invasive treatment• Therapeutic localized delivery• Localized cell kill• Lower dose administered• Improved side effect profile

Clinical Applications Using NanoparticlesClinical Applications Using Nanoparticles

Alivisatos et al.

Q-dots

Nanocrystals for E-chem det.

Nicewarner-Pena et al., Science 294, 137 (2001)

J. Wang, Analytica ChimicaActa 500 (2003) 247

Multiplexed Diagnostic AssaysMultiplexed Diagnostic Assays

G. Wu and A. Majumdar, Nature Biotech 19, 856 (2001)

Nanorods

Cantilevers

In-vitro DiagnosticBiomarker Recognition

Single-Walled Carbon Nanotubes in Biological ApplicationsSingle-Walled Carbon Nanotubes in Biological Applications

• Bio events electrical signals• Single tube detects parts-per-billion

(NO2)• Extreme surface/volume ratio• Protein binding affects electrical

property of nanotubes• Label-free, electronic readout

• Sensitive, specific, and multiplex detections of biological molecules• Unusually bright as Raman-labels:

~10fM sensitivity• Near single molecule detection• No need for amplification steps• No interfering background• Stable signal, no quenching

200 nm

Hongjie Dai, Stanford CCNE

Gao and Nie, Nature Biotech 22, 969 (2004)

Human prostate cancer growing in nude mice

QDs functionalized with PSMA

Multi-color imaging using the same excitation source

Quantum Dots for In-vivo ImagingQuantum Dots for In-vivo Imaging

Wide range of wavelength coverage using different materials

In vivo fluorescence images of tumor using QD probes Michalet and Gambhir, Science 307, 538 (2005)

In-vivo DiagnosticImaging of Tumor

Tissue

Novel Quantum Dots That Do Not Require External IlluminationNovel Quantum Dots That Do Not Require External Illumination

• Quantum dots conjugated with fluorescent proteins bioluminesce in response to an enzyme-catalyzed reaction

• Bioluminescence resonance energy transfer (BRET) is shown for the first time with quantum dots

• Blood does not interfere with quantum dot signal

So, Gambhir, Rao et al., Self-illuminating quantum dot conjugates for in vivo imaging,Nat. Biotechnol. 24, 339 (2006)

Nanoparticles (dextran-coated iron oxide crystals, Combidex) injected into the circulation travel to the lymph nodes. Metastatic tumors growing in the nodes interfere with particle distribution, and this is detectable by MRI. 80 men undergoing surgery or biopsy for prostate cancer had MRI exams both with and without the nanoparticles before surgery. 33 of the men actually had metastatic lymph nodes. MRI with the particlesidentified all 33, whereas MRI without the particles missed more than half of them.

image reconstructiongreen: normalred: malignant

malignant

normal

Conventional MRI

Nanoparticle imaging

NEJM, 2003, 348:2491-2499

Nanoparticle-based Detection of Lymph Node MetastasisNanoparticle-based Detection of Lymph Node Metastasis

Ralph Weissleder (MGH, Harvard Medical School) Jean de la Rosette (Netherlands)

Magnetic Nanoparticles for Ultra-Sensitive Magnetic Resonance Imaging

Magnetic Nanoparticles for Ultra-Sensitive Magnetic Resonance Imaging

12 nm size of various ferrite nanoparticles

Cheon et al. Nature Medicine 2007, 13, 95Tom Meade et al, Northwestern U.

Multi-Functional Nanoparticle-based TherapiesMulti-Functional Nanoparticle-based Therapies

• Multi-functional platforms: • Targeting• Delivery• Reporting, biosensing

In one package

Free drug formulations do not possess multi-functional

characteristics

First generation of nano-delivered drugs (no targeting) approved by FDA – Abraxane®

M. Ferrari, Nature Reviews 5, 161 (2005)

Nanoshells:Photothermal therapy

N. Halas, J. West et al, Ann Biomed Eng. 34, 15 (2006)

Dendrimers: Targeted delivery of methotrexate

Nanoparticle-based Therapies: Different ApproachesNanoparticle-based Therapies: Different Approaches

J. Baker, et al., Cancer Res. 65, 5317 (2005)

Docetaxel-Encapsulated PLGA Nanoparticle-AptamerConjugatesDocetaxel-Encapsulated PLGA Nanoparticle-AptamerConjugates

Aptamers are non-immunogenic chemically processed DNA or RNA oligonucleotides that bind to antigen with high affinity and specificity; nanopaticle-aptamer conjugates have been developed for Prostate Specific Membrane Antigen (PSMA)

Farokhzad, Cheng, Langer et al., Targeted nanoparticle-aptamer bioconjugatesfor cancer chemotherapy in vivo, Proc Natl Acad Sci 103, 6315 (2006)

NP-Apt Conjugates: Comparative Efficacy StudyNP-Apt Conjugates: Comparative Efficacy Study

LNCaP s.c. xenograft nude mouse model of PCa; single intratumoral injection (day 0)

NP-Apt conjugates show greater efficacy in a xenograft mouse model than non-targeted nanoparticles

PRINTTM Particles: CDI-Activated PEG for Functional Targeting

PRINTTM Particles: CDI-Activated PEG for Functional Targeting

O

O

N N

O

O

NN

OO

N

N

O

O

NN

OO

N

N

O

ON

N

Multiplexed Delivery of Targeted Anticancer Agents

Joe DeSimone, UNC

Nanotechnology:Environmental and Safety ConsiderationsNanotechnology:Environmental and Safety Considerations

Nanomaterials

production

Chronic exposure

of the worker

Nanomaterialsuse for biomedical applications

Preclinical studies

• Hazard identification• In vitro toxicity• Acute in vivo toxicity• Subchronic/chronic toxicity• Route of exposure

• Dose response• External dose• Internal dose• Biologically effective dose

• Exposure assessment• Human exposure

NCL Concept of OperationsNCL Concept of Operations

NCL is a formal collaboration between NCI, FDA and NIST

Current StatusCurrent Status

• Development of new diagnostic and therapeutic platforms is at different levels of maturity

• Two drugs approved by FDA: 1) Abraxane – paclitaxelbound to albumin (Abraxis Bioscience) and 2) Doxil –liposome encapsulated doxorubicin

• Common scheme for therapeutics – use existing drugs and adapt them to nano-based delivery platform

• In-vitro diagnostic tools to evaluate clinical samples

• Several companies (2-5) ready to file IND within next 12 months

Future prospectsFuture prospects

• Broader engagement of oncologists in the technology development is needed

• Are multi-functional (target, reporter, and therapy) solutions practical or too complex?

• Can the development of new drugs benefit from nanotechnology?• New screening methods• New formulations?

• Combination of in-vivo diagnosis and tailored therapy

Travis Earles

Jerry Lee

Linda Molnar

Larry Nagahara

Acknowledgements: NCI Nanotechnology Program OfficeAcknowledgements: NCI Nanotechnology Program Office